Antihypercholesterolemic agents have evolved rapidly since hypercholesterolemia was well recognized as a primary risk factor in atherosclerotic and cardiovascular diseases.
A class of drugs, such as 3-hydroxy-3-methylglutaryl-CoA reductase (HMG-CoA reductase) inhibitors, as called statins, is currently potent antihypercholesterolemic agents. (Cai Zhengyang, Zhou Weicheng. Progresses in researches of HMG-CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911).
The launched drugs, lovastatin, simvastatin, pravastatin, fluvastatin, atorvastatin, rosuvastatin, and pitavastatin are currently available antihypercholesterolemic agents.
In the prior arts, the structure of totally synthetic statins is composed of a framework such as quinoline, indole, pyrrole, pyrimidime and a side chain.
Systematical QSAR studies on quinoline statin compounds, such as pitavastatin, show that the introduction of the side chains to position 3 in quinoline exhibited a good activity in inhibiting HMG-CoA reductase. The introduction of chloro, methyl or methoxy etc. to the 6-, 7- or 8-position of the quinoline nucleus may increase the inhibitory potency. (Cai Z-Y, Zhou W-C. Progresses in researches of HMG-CoA reductase inhibitors, Chinese Journal of New Drugs, 2006, 15 (22): 1907-1911).
The Chinese patent applications, No. 200610148118.4 and 200710036427.7, disclosed the quinoline derivatives in which a thiophenyl and a phenoxy was introduced to position 4 respectively, and the side chains have a lactone structure. Both of said quinoline derivatives demonstrate a good activity in inhibiting HMG-CoA reductase in vitro experiments. However, as far as human requirement is concerned, there is a need to develop new potent antihypercholesterolemic drugs.